Major depression is frequently co-morbid with cancer. The biological component of this relationship has not yet been established and depression is essentially viewed as a factor that primarily affects quality of life in cancer patients. Whether the influence of the states of depression goes beyond their effect on the quality of life and directly affects molecular and cellular mechanisms of resistance to tumor growth remains to be established. Here we propose a novel approach, which would investigate the effect of clinical depression and its reversal on factors that control the response to antitumor therapy and ultimately tumor progression and outcome of the disease. In particular, we propose to study factors that modify vulnerability of normal cells to genotoxic stress during reversal of the depressive state in breast cancer patients with prior history of chemotherapy and/or irradiation. We will focus on two of the targets most vulnerable to genotoxic stress, leukocytes and hematopoietic progenitor ceils which not only constitute the immune system but also contribute to natural resistance to tumors and are involved in cellular homeostasis in general. The susceptibility of these cells to apoptosis will be evaluated by the expression profiling of apoptosis-related genes and the corresponding proteins. We will also investigate the putative effect of plasma factors in depressed subjects on the signal transduction machinery involved in the cell response to environmental stress which will be determined by screening plasma samples in various specially designed cellular reporter systems in vitro. As a pilot project, this proposal is limited to reversal of the depressive state by pharmacotherapy as the most rational approach for a short term/moderate budget study. The data generated in this study will be applied to a larger project focused on the effect of non-pharmacological therapy for depression in comparison with conventional antidepressants on susceptibility of normal cells to environmental stress. This will provide insight as to whether biological changes at the cellular level are caused by the modulation of specific neurochemical and neuroendocrine pathways which are targeted by conventional antidepressants or by as yet unidentified putative factors that constitute biological features of the depressive state in cancer patients. The results of this study may provide justification for consideration of mood-modifying therapy as an adjuvant therapy in cancer.